Glial cells maintain synapses by inhibiting an activity-dependent retrograde protease signal

Thomas W. Gould, Bertha Dominguez, Fred de Winter, Gene W. Yeo, Patrick Liu, Balaji Sundararaman, Thomas Stark, Anthony Vu, Jay L. Degen, Weichun Lin, Kuo-Fen Lee, Gregory A. Cox
2019 PLoS Genetics  
Glial cells regulate multiple aspects of synaptogenesis. In the absence of Schwann cells, a peripheral glial cell, motor neurons initially innervate muscle but then degenerate. Here, using a genetic approach, we show that neural activity-regulated negative factors produced by muscle drive neurodegeneration in Schwann cell-deficient mice. We find that thrombin, the hepatic serine protease central to the hemostatic coagulation cascade, is one such negative factor. Trancriptomic analysis shows
more » ... expression of the antithrombins serpin C1 and D1 is significantly reduced in Schwann cell-deficient mice. In the absence of peripheral neuromuscular activity, neurodegeneration is completely blocked, and expression of prothrombin in muscle is markedly reduced. In the absence of muscle-derived prothrombin, neurodegeneration is also markedly reduced. Together, these results suggest that Schwann cells regulate NMJs by opposing the effects of activity-regulated, muscle-derived negative factors and provide the first genetic evidence that thrombin plays a central role outside of the coagulation system.
doi:10.1371/journal.pgen.1007948 pmid:30870413 pmcid:PMC6417855 fatcat:jfadv7riyvddbfivhsjbuqqhfi